Bupivacaine injection remodels extraocular muscles and corrects comitant strabismus.

PURPOSE: To evaluate the clinical effectiveness and anatomic changes resulting from bupivacaine injection into extraocular muscles to treat comitant horizontal strabismus. DESIGN: Prospective, observational clinical series. PARTICIPANTS: Thirty-one comitant horizontal strabismus patients. METHODS: Nineteen patients with esotropia received bupivacaine injections in the lateral rectus muscle, and 12 patients with exotropia received bupivacaine injections in the medial rectus. Sixteen of these, with large strabismus angles, also received botulinum type A toxin injections in the antagonist muscle at the same treatment session. A second treatment was given to 13 patients who had residual strabismus after the first treatment. MAIN OUTCOME MEASURES: Clinical alignment measures and muscle volume, maximum cross-sectional area, and shape derived from magnetic resonance imaging, with follow-up examinations for up to 3 years. RESULTS: At an average of 15.3 months after the final treatment, original misalignment was reduced by 10.5 prism diopters (Δ; 6.0°) with residual deviations of 10Δ or less in 53% of patients. A single treatment with bupivacaine alone reduced misalignment at 11.3 months by 4.7Δ (2.7°) with residual deviations of 10Δ or less in 50% of patients. Alignment corrections were remarkably stable over follow-ups for as long as 3 years. Six months after bupivacaine injection, muscle volume had increased by 6.6%, and maximum cross-sectional area had increased by 8.5%, gradually relaxing toward pretreatment values thereafter. Computer modeling with Orbit 1.8 (Eidactics, San Francisco, CA) suggested that changes in agonist and antagonist muscle lengths were responsible for the enduring changes in eye alignment. CONCLUSIONS: Bupivacaine injection alone or together with botulinum toxin injection in the antagonist muscle improves eye alignment in comitant horizontal strabismus by inducing changes in rectus muscle structure and length.

Dual encoding of muscle tension and eye position by abducens motoneurons.

Extraocular muscle tension associated with spontaneous eye movements has a pulse-slide-step profile similar to that of motoneuron firing rate. Existing models only relate motoneuron firing to eye position, velocity and acceleration. We measured and quantitatively compared lateral rectus muscle force and eye position with the firing of abducens motoneurons in the cat to determine fundamental encoding correlations. During fixations (step), muscle force increased exponentially with eccentric eye position, consistent with a model of estimate ensemble motor innervation based on neuronal sensitivities and recruitment order. Moreover, firing rate in all motoneurons tested was better related to eye position than to muscle tension during fixations. In contrast, during the postsaccadic slide phase, the time constant of firing rate decay was closely related to that of muscle force decay, suggesting that all motoneurons encode muscle tension as well. Discharge characteristics of abducens motoneurons formed overlapping clusters of phasic and tonic motoneurons, thus, tonic units recruited earlier and had a larger slide signal. We conclude that the slide signal is a discharge characteristic of the motoneuron that controls muscle tension during the postsaccadic phase and that motoneurons are specialized for both tension and position-related properties. The organization of signal content in the pool of abducens motoneurons from the very phasic to the very tonic units is possibly a result of the differential trophic background received from distinct types of muscle fibers.

Motor nucleus activity fails to predict extraocular muscle forces in ocular convergence.

For a given eye position, firing rates of abducens neurons (ABNs) generally (Mays et al. 1984), and lateral rectus (LR) motoneurons (MNs) in particular (Gamlin et al. 1989a), are higher in converged gaze than when convergence is relaxed, whereas LR and medial rectus (MR) muscle forces are slightly lower (Miller et al. 2002). Here, we confirm this finding for ABNs, report a similarly paradoxical finding for neurons in the MR subdivision of the oculomotor nucleus (MRNs), and, for the first time, simultaneously confirm the opposing sides of these paradoxes by recording physiological LR and MR forces. Four trained rhesus monkeys with binocular eye coils and custom muscle force transducers on the horizontal recti of one eye fixated near and far targets, making conjugate saccades and symmetric and asymmetric vergence movements of 16-27°. Consistent with earlier findings, we found in 44 ABNs that the slope of the rate-position relationship for symmetric vergence (k(V)) was lower than that for conjugate movement (k(C)) at distance, i.e., mean k(V)/k(C) = 0.50, which implies stronger LR innervation in convergence. We also found in 39 MRNs that mean k(V)/k(C) = 1.53, implying stronger MR innervation in convergence as well. Despite there being stronger innervation in convergence at a given eye position, we found both LR and MR muscle forces to be slightly lower in convergence, -0.40 and -0.20 g, respectively. We conclude that the relationship of ensemble MN activity to total oculorotary muscle force is different in converged gaze than when convergence is relaxed. We conjecture that LRMNs with k(V) < k(C) and MRMNs with k(V) > k(C) innervate muscle fibers that are weak, have mechanical coupling that attenuates their effective oculorotary force, or serve some nonoculorotary, regulatory function.

EOM Pulleys and Sequelae: A Critical Review.

Purpose: The discovery of extraocular muscle (EOM) pulleys resolved long-standing issues in oculomotor physiology, revived interest in EOM function generally, and led to several new theories. We describe the pulley concept of Miller and Demer (M-D Pulleys) and briefly review evidence, distinguishing this well-supported notion from the Active Pulley Hypothesis (APH) and the EOM Compartments hypothesis, and critically reviewing the methodologies and evidence on which the latter are based. Methods: We analyze evidence on mechanical independence of individual EOM fibers, implications of nerve tracing for functional independence of EOM layers and compartments, validity of image-based methods of assessing EOM contraction, and data analysis issues. Conclusions: M-D Pulleys are well-supported by several lines of evidence from several labs. The APH, which predicts relative movements of EOM lamina sufficient to alter muscle actions, has been effectively disproved. The width-wise articulations of EOM Compartments, in contrast, might produce significant contractile oculorotary force gradients across muscle tendons, although existing evidence is unconvincing. We suggest how this hypothesis could be effectively tested.

Activating the levator to elevate the eyelid.

PURPOSE: To demonstrate in an animal model the feasibility of elevating the eyelid in a functionally useful manner by chronically stimulating the levator palpebrae superioris (LPS) muscle with an implanted electrode. METHODS: Five rabbits were implanted with electrodes designed to stimulate the nerve innervating the LPS near its entry to the muscle. Bipolar platinum electrodes in a silicone rubber envelope with silicone-sleeved, PTFE-coated platinum lead wires were used to provide long-term stimulation with bipolar square-wave pulse trains of 0.18-0.80 mA and 200 Hz at a duty cycle of 8 seconds on and 2 seconds off. Explanted electrodes were examined for damage, and stimulated tissues were evaluated for abnormalities by light microscopy. RESULTS: We achieved mean lid elevation of 1.6 mm, approaching the diameter of the light-adapted pupil, with 0.5 mA stimulus. Stimulus currents below 1.0 mA produced no signs of discomfort. Three animals with which we attempted daily stimulation, averaged 16.1 hours per week. Experiments lasted 22 weeks on average. Lid lifting with a well-implanted platinum electrodes was stable, with no apparent tissue or electrode damage after as long as 29.1 weeks. CONCLUSIONS: Stable, functionally useful eyelid lifting was achieved with stimulation currents that caused no apparent discomfort or damage to muscles or nerves. A simple, discrete bipolar electrode was effective and survivable.

Bupivacaine injection of eye muscles to treat strabismus.

BACKGROUND: Bupivacaine injected into animal muscles induces a cycle of myotoxicity, degeneration, regeneration and hypertrophy of muscle fibres, without adverse effects on other tissues. This induced hypertrophy can be harnessed to treat strabismus. METHODS: Bupivacaine, 4.5 ml of a 0.75% solution, was injected into the right lateral rectus (RLR) muscle of a patient who had diplopia and who showed 14-prism-dioptres oesotropia. RESULTS: RLR paresis persisted for 7 days. Then, the RLR regained its abducting ability, and progressive improvement of alignment to 4-prism-dioptres oesophoria occurred over the next 33 days, with the elimination of diplopia. Alignment remained the same at 54 days after injection. Magnetic resonance imaging showed a focal increase in the size of the injected RLR of 58% in the posterior area, with reduced change in anterior portions of the RLR. CONCLUSION: Injection of bupivacaine to induce hypertrophy of the injected muscle and thus alter eye alignment was effective in our patient. This approach can be a useful addition to the treatment of strabismus.

Understanding and misunderstanding extraocular muscle pulleys.

As evidence has mounted for the critical role of extraocular muscle (EOM) pulleys in normal ocular motility and disease, opposition to the notion has grown more strident. We review the stages through which pulley theory has developed, distinguishing passive, coordinated, weak differential, and strong differential pulley theories and focusing on points of controversy. There is overwhelming evidence that much of the eye's kinematics, once thought to require brainstem coordination of EOM innervations, is determined by orbital biomechanics. The main criticisms of pulley theory only apply to the strong differential theory, abandoned in 2002. Critiques of the notion of dual EOM insertions are shown to be mistaken. The role of smooth muscle and the issue of rotational noncommutativity are clarified. We discuss how pulley sleeves can be stabilized as required by the theory, noting that more work needs to be done in specifying the tissues involved.

Stability of gold bead tissue markers.

Significant soft tissue features in the orbit and elsewhere are not resolved by MRI or any other imaging method. We describe a new method that uses tiny ( approximately 0.1 mm diameter) gold beads as markers to visualize movements of such tissues with high spatial resolution ( approximately 100 microm) and moderate temporal resolution ( approximately 100 ms). We describe bead fabrication, implantation, imaging, and image processing to extract three-dimensional bead coordinates. We then present results of an experiment to determine the stability of gold bead tissue markers (GBTMs) over time in normally moving orbital tissues. Most beads (76%) implanted in sclera, muscle, tendon, and connective tissue were highly stable over the 6-month measurement period. Beads that were judged unstable drifted only a few 100 microm. Bead flows with gaze suggested that posterior Tenon's capsule moves with the globe, that the lateral rectus belly may sideslip, producing "bridle forces," and that the posterior medial rectus pulley sling moves freely anteriorly and posteriorly, but hardly vertically, as required by the "coordinated active pulley" hypothesis. The GBTM method seems applicable to study such short time course phenomena as extraocular muscle (EOM) and connective tissue movement as a function of gaze and such long time course phenomena as myopic eye growth.

Pharmacologic injection treatment of comitant strabismus.

PURPOSE: To report the magnitude and stability of corrections in comitant horizontal strabismus achieved by injecting bupivacaine (BPX, optionally with epinephrine) and botulinum A toxin (BTXA) into extraocular muscles of alert adult subjects with electromyographic (EMG) guidance. METHODS: A total of 55 adults with comitant horizontal strabismus participated in a prospective observational clinical series. Of these, 29 previously had undergone 1 or more unsuccessful strabismus surgeries; 4 had undergone other orbital surgeries. Thirty-one patients with esodeviations received BPX injections in a lateral rectus muscle, some with BTXA in the medial rectus; 24 patients with exodeviations received BPX in a medial rectus muscle, some with BTXA in the lateral rectus muscle. A second treatment (BPX, BTXA, or both) was administered to 27 patients who had residual strabismus after the first treatment. Five patients required additional injections. Clinical alignment was measured at 6 months and yearly thereafter through 5 years' follow-up, with mean follow-up of 28 months. A successful outcome was defined as residual deviation ≤10(Δ). RESULTS: On average, presenting misalignment of 23.8(Δ) (13.4°) was reduced at 28 months by 16.0(Δ) (9.1°), with successful outcomes in 56% of patients. Of patients with initial misalignments ≤25(Δ), 66% had successful outcomes, with corrections averaging 13.2(Δ) (7.5°); of patients with larger misalignments, 40% had successful outcomes, with corrections averaging 20.9(Δ) (11.8°). Corrected alignments were stable over follow-ups as long as 5 years. CONCLUSIONS: Injection treatments resulted in stable, clinically significant corrections in comitant horizontal strabismus. Injection provides a low-cost alternative to incisional strabismus surgery, particularly where it is desirable to minimize surgical anesthesia and avoid extraocular scarring.

Extraocular connective tissue architecture.

Extraocular muscle pulleys, now well known to be kinematically significant extraocular structures, have been noted in passing and described in fragments several times over the past two centuries. They were late to be fully appreciated because biomechanical modeling of the orbit was not available to derive their kinematic consequences, and because pulleys are distributed condensations of collagen, elastin and smooth muscle (SM) that are not sharply delineated. Might other mechanically significant distributed extraocular structures still be awaiting description?An imaging approach is useful for describing distributed structures, but does not seem suitable for assessing mechanical properties. However, an image that distinguished types and densities of constituent tissues could give strong hints about mechanical properties. Thus, we have developed methods for producing three dimensional (3D) images of extraocular tissues based on thin histochemically processed slices, which distinguish collagen, elastin, striated muscle and SM. Overall tissue distortions caused by embedding for sectioning, and individual-slice distortions caused by thin sectioning and subsequent histologic processing were corrected by ordered image warping with intrinsic fiducials. We describe an extraocular structure, partly included in Lockwood's ligament, which contains dense elastin and SM bands, and which might refine horizontal eye alignment as a function of vertical gaze, and torsion in down-gaze. This active structure might therefore be a factor in strabismus and a target of therapeutic intervention.

Extraocular muscle motor units characterized by spike-triggered averaging in alert monkey.

Single-unit recording in macaque monkeys has been widely used to study extraocular motoneuron behavior during eye movements. However, primate extraocular motor units have only been studied using electrical stimulation in anesthetized animals. To study motor units in alert, behaving macaques, we combined chronic muscle force transducer (MFT) and single-unit extracellular motoneuron recordings. During steady fixation with low motoneuron firing rates, we used motoneuron spike-triggered averaging of MFT signals (STA-MFT) to extract individual motor unit twitches, thereby characterizing each motor unit in terms of twitch force and dynamics. It is then possible, as in conventional studies, to determine motoneuron activity during eye movements, but now with knowledge of underlying motor unit characteristics. We demonstrate the STA-MFT technique for medial rectus motor units. Recordings from 33 medial rectus motoneurons in three animals identified 20 motor units, which had peak twitch tensions of 0.5-5.25mg, initial twitch delays averaging 2.4 ms, and time to peak contraction averaging 9.3 ms. These twitch tensions are consistent with those reported in unanesthetized rabbits, and with estimates of the total number of medial rectus motoneurons and twitch tension generated by whole-nerve stimulation in monkey, but are substantially lower than those reported for lateral rectus motor units in anesthetized squirrel monkey. Motor units were recruited in order of twitch tension magnitude with stronger motor units reaching threshold further in the muscle's ON-direction, showing that, as in other skeletal muscles, medial rectus motor units are recruited according to the "size principle".

Treating strabismus by injecting the agonist muscle with bupivacaine and the antagonist with botulinum toxin.

PURPOSE: We report the results of injection of bupivacaine (BUP) and botulinum toxin (BT) into agonist and antagonist muscles, respectively, to treat horizontal strabismus. METHODS: We treated both horizontal muscles of 7 patients with comitant horizontal strabismus, 2 patients with partial lateral rectus (LR) paralysis, and one elderly myopic patient with acquired esotropia, injecting the agonist muscle with BUP in concentrations of 0.75% to 3.0% and volumes of 3.0 to 5.0 mL, and the antagonist with BT in about half the usual therapeutic dose to prevent it from stretching the BUP-treated muscle during its regeneration following BUP myotoxicity. We reinjected BT in one patient who had an inadequate response from the initial BT dose. RESULTS: The 7 comitant patients were corrected (on average) 19.7 prism diopters (Delta), from 28.3Delta to 8.6Delta, at 193 days after injection. Muscle volume increase after BUP injection was 5.8% at 158 days. One LR palsy patient without LR atrophy was changed 55Delta; the other, with LR atrophy, was corrected 4Delta. Two patients had transient vertical deviations from the BT injection. The myopic patient with esotropia was unchanged. CONCLUSIONS: Injections of BUP and BT corrected 7 patients with comitant horizontal strabismus an average of 19.7Delta, about double the correction reported from BUP injection alone. BUP-injected muscles increased size by 5.8%. Of 2 patients with LR weakness, one without LR atrophy was changed by 55Delta, but another with LR atrophy was corrected only 4Delta.

Bupivacaine injection of the lateral rectus muscle to treat esotropia.

PURPOSE: We report results of a pilot trial of bupivacaine injection into extraocular muscles as a method of enlarging and strengthening the muscles to treat strabismus. METHODS: Bupivacaine, in volumes from 1.0 to 4.5 mL and concentrations from 0.75% to 3.0%, was injected into 1 lateral rectus muscle in each of 6 patients with comitant esotropia with the use of the electrical activity recorded from the needle tip to guide injection. Magnetic resonance imaging was performed before and at intervals after injection to estimate changes in muscle size. Clinical measures of alignment were made before and at intervals after injection. Two patients required a second injection for adequate effect. RESULTS: Four patients showed improved eye alignment, averaging 12(Delta), measured an average of 367 days after the last injection (range, 244-540 days). Two patients were substantially unchanged. Alignment improvement for all 6 patients averaged 8(Delta) (range, 0-14(Delta)). Volumetric enlargement of the injected muscle, computed from magnetic resonance images, was 6.2% (range, -1.5% to 13.3%). There was a positive correlation between alignment change and muscle enlargement averaging 0.65. Injection caused a retrobulbar hemorrhage in an unchanged patient that cleared without affecting vision. CONCLUSIONS: Bupivacaine injection improved eye alignment in 4 of 6 esotropic patients. There was a positive correlation between improved eye alignment and increased muscle size. Clinical and laboratory studies are underway to determine optimal dosages, effects in other strabismus conditions, and differential effects of bupivacaine on contractile and elastic muscle components.

Missing lateral rectus force and absence of medial rectus co-contraction in ocular convergence.

For a given position of the eye in the orbit, most abducens motoneurons (LRMNs) fire at higher rates in converged gaze than when convergence is relaxed, implying that lateral rectus (LR) muscle force will be higher for a given eye position in convergence. If medial rectus (MR) muscle force balances LR force, it too would be higher in convergence, that is, LRMN recording studies predict horizontal rectus co-contraction in convergence. Three trained rhesus monkeys with binocular eye coils and custom muscle force transducers (MFTs) on LR and MR of one eye alternately fixated near (approximately 7 cm) and far (200 cm) targets with vergence movements of 20-30 degrees. Tonic muscle forces were also measured during conjugate fixation of far targets over a 30 x 30 degrees field. MFT characteristics and effects on oculomotility were assessed. Contrary to predictions, we found small (<1 g) decreases in both LR and MR forces in convergence, for those gaze positions that were used in the brain stem recording studies. This missing LR force paradox (higher LRMN firing rates in convergence but lower LR forces) suggests that motoneurons or muscle fibers contribute differently to oculorotary forces in converged and unconverged states, violating the final common path hypothesis. The absence of MR co-contraction is consistent with, and supports, the missing LR force finding. Resolution of the missing LR force paradox might involve nonlinear interactions among muscle fibers, mechanical specialization of muscle fibers and other articulations of the peripheral oculomotor apparatus, or extranuclear contributions to muscle innervation.